Double salts of (-)-hydroxycitric acid with an amine and a group II a metal and a process for preparing the same

ABSTRACT

This invention relates to novel double salt of (−)-hydroxycitric acid with an amine and zinc or a group II A metal. These compounds are stable and water soluble and are used as nutraceuticals, weight reducing agents and in beverages. The double salts have the following general formula (I) Wherein X is zinc or a metal belonging to group II A of the Periodic Table and Y is glucosamine, caffeine or a known anorexic amine residue.

This invention relates to double salts of (−)-hydroxycitric acid with anamine and a group II A metal and a process for preparing the same.

TECHNICAL FIELD

The (−)-hydroxycitric acid (HCA) is a naturally occurring fruit acidfound in the rinds of the fruit of Garcinia cambogia (family:Guttiferae), a tree that is native to Southeast Asia and also found inother Garcinia species like Garcinia indica and Garcinia mangostana. Thedried fruit rind of G. cambogia, also known as Malabar tamarind, iscommonly used in Southeast Asia (particularly southern India) as a foodpreservative, flavoring agent and carminative. The primary mechanism ofaction of (−)-HCA appears to be related to act as a competitiveinhibitor of the enzyme ATP-citrate lyase, which catalyzes theconversion of citrate and coenzyme A to oxaloacetate and acetyl coenzymeA (acetyl-CoA). Extensive experimental studies suggest that (−)-HCAsuppresses the fatty acid synthesis, lipogenesis and food intake thusleading to weight reduction. In addition to suppression of fatty acidand fat synthesis, (−)-HCA is thought to suppress food intake via lossof appetite by stimulation of liver gluconeogenesis. Various researchershave evaluated HCA for its weight control properties, fat burningproperties, lipid level lowering effect, appetite regulation, metabolicrate increase and other effects. A number of patents have been grantedbased on the above studies and various methods of extraction of HCA fromthe fruit. The isolation and chemical nature of (−)-hydroxycitric acidfrom Garcinia rind are described in the publication of Lewis, Y. S. etal, Phytochemistry, 4, 619-625 (1965). Moffett, et al., U.S. Pat. No.5,656,314 (1997) described a process for the aqueous extraction of(−)-HCA from Garcinia rinds.

It has been found that the free acid form of (−)-hydroxycitric acid isunstable, forming lactone (FIG. 1) which generally do not possess thedesired bioactivity and also the liquid form of HCA tends to be unstableduring storage. Therefore, food preparations that incorporate the freeacid in liquid form will not provide the full benefit of the HCA in thefinal preparation.

A number of patents have been granted for the preparation of(−)-hydroxycitric acid salts. Singh, et al., Biol. Memoirs, 21, 27-33(1995), describes the preparation of calcium salt of HCA. The drawbackof this salt is not very soluble in water. Majeed, et al., U.S. Pat. No.5,783,603 (1998), disclosed the preparation of potassium salt of HCA;but it is hygroscopic and has strong pungent taste. Ganga Raju, G. PCTPublication No. WO 99/03464 (28 Jan., 1999) described the preparation ofcalcium and potassium or sodium double salts of HCA and its use asdietary supplements and food products to reduce body weight.Balasubramanyam, et al., U.S. Pat. No. 6,160,172 (2000) disclosed thepreparation of similar double salts of HCA.

Calcium gives bones their strength, while magnesium helps them maintaintheir elasticity to prevent injury. The more calcium in the diet, themore magnesium that is needed. Calcium given alone can induce amagnesium deficiency. The most serious complications from a deficiencyof magnesium are heart conditions such as irregular heartbeat and rapidheartbeat (Bariscode, M. et al., American Journal of Nutrition, 1996,19, 296). The magnesium recommended in USA by the Daily Reference Intake(DRI) is 420 mg for male adults and 330 mg for female adults. So it isgood to have good calcium and magnesium in our daily diet or supplement.Shrivatstava, et al, U.S. Pat. No. 6,221,901 (2001) disclosed themagnesium (−) hydroxycitrate as dietary nutritional supplement.

Zinc is an essential mineral that is found in almost every cell. It isneeded for wound healing, sense of taste and smell, DNA synthesis and itsupports normal growth and development during pregnancy, childhood andadolescence. The DRI's of zinc for adult male is 11 mg and for adultfemale is 8 mg.

Glucosamine (an amino saccharide) helps in strengthening the jointstructure thereby improving mobility. So far four sources of glucosamineare reported namely glucosamine hydrochloride, glucosamine hydroiodide,glucosamine sulphate and N-acetyl glucosamine. Of these, glucosaminesulfate is the most preferred form of glucosamine and is widely used inthe treatment of osteoarthritis and other acute and chronic forms ofrheumatic and arthritic diseases. This salt in the market-place islabeled as ‘glucosamine sulfate’ or ‘stabilized glucosamine sulfate’,contains potassium or sodium chlorides. Ravi Gajanan, B et al, CA2436925 (2002) and Schleck, et al, U.S. Pat. No. 5,902,801 (1999)described the preparation of glucosamine sulfate metal chloride byreacting glucosamine hydrochloride with metal sulfate.

Now we have invented, stable water soluble glucosamine (−)-hydroxycitricacid salts, which can be used both for arthritic diseases and to reducebody weight, since obese persons also suffer from arthritic diseases.

DISCLOSURE OF THE INVENTION

The invention relates to double salts of (−)-hydroxycitric acid with anamine and zinc or a group II A metal having the following generalformula

Wherein X is zinc or a metal selected from group II A of the PeriodicTable and Y is glucosamine residue or caffeine or any known anorexicamine residue such as aminorex (4,5-dihydro-5-phenyl-2-oxazolamine),clobenzorex ((+)-N-[(2-chlorophenyl)methyl]-α-methylbenzeneethanamine),cyclexedrine (N,β-dimethylcycohexaneethanamine), diphemethoxidine(2-(diphenylmethyl)-1-piperidineethanol), fenbutrazate(α-ethylbenzeneacetic acid 2-(3-methyl-2-phenyl-4-morpholinyl)ethylester), fenproporex (3-[(1-methyl-2-phenylethyl)-amino]propanenitrile),furfurylmethylamphetamine(N-methyl-N-(1-methyl-2-phenylethyl)-2-furanmethanamine),levophacetoperane (α-phenyl-2-piperidinemethanol acetate), mefenorex(N-(3-chloropropyl)-α-methylbenzeneethanamine), metamfepramone(2-(dimethylamino)-1-phenylpropanone), norpseudoephedrine(threo-2-amino-1-hydroxy-1-phenylpropane), pentorex(α,α,β-trimethylbenzeneethanamine), picilorex(3-(4-chlorophenyl)-5-cyclopropyl-2-methylpyrrolidine), sibutramine(1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)cyclobutanemethanamine)or phenylpropanolamine (2-amino-1-phenyl-1-propanol).

Preferably, this invention relates to double salts of (−)-hydroxycitricacid of the general formula 2 given below:

Wherein X is a group II A metal or zinc.

The new compounds according to this invention may be prepared by thefollowing processes:

-   -   (a) by reacting (−)-hydroxycitric acid hereinafter referred as        HCA with glucosamine and a compound containing zinc or group II        A metal of the Periodic Table.    -   (b) by reacting calcium or magnesium or zinc and        potassium/sodium double salts of HCA with glucosamine        hydrochloride.

In the first process, stoichiometric equivalents of the reactants aremixed to obtain the desired double salts. Preferably, the reaction isinitiated by the slow addition of glucosamine free base to an aqueoussolution of HCA followed by the metal compound. Hydroxycitric acid maybe obtained by a known process of extraction from the fruits of Garciniaspecies. The purified and enriched (−)—HCA may be obtained by convertingwater extract of the rind into insoluble calcium salt and convertingback to HCA using phosphoric acid (Ganga Raju, G, PCT Publication No. WO99/03464) or by passing the water extract of the fruit through ionexchange columns as described in U.S. Pat. No. 6,160,172.

Preferred metals selected are calcium, magnesium and zinc and thesemetal compounds are selected from their carbonates or hydroxides.Glucosamine base may be liberated from glucosamine hydrochloride byanionic exchange treatment.

The double salts prepared by this process may contain between 40 to 60%of HCA, 10-35% of glucosamine and 5-10% of the metal.

According to the second process of preparing the compounds of thisinvention, stoichiometric quantities of potassium/sodium and calciumdouble salts of HCA and glucosamine hydrochloride are reacted in aqueousmethanol medium.

Compounds of this invention containing any amino substituents may beprepared by replacing glucosamine with the corresponding aminocompounds.

Preferred compounds selected having amino residues are glucosamine,caffeine, norephedrine or sibutramine. The compounds according to thisinvention exhibit good water solubility, no taste or odour and arestable in comparison with the naturally occurring HCA.

Preferred embodiments of the processes of preparing the compounds ofthis invention are given in the following examples, which are in no wayrestrictive. These examples produce the compounds of this invention inhigh purity of more than 95%.

EXAMPLE 1

Calcium, glucosamine double salt of (−)—HCA: To an aqueous garciniasolution (27 mL, 2.0 g, 1.0 equivalent) was added glucosamine free basesolution (100 mL, 1.7 g, 1.0 equivalent) and stirred for 1 h. Thencalcium hydroxide (708 mg, 1.0 equivalent) was added and after stirringfor 2 h, charcoal (0.5 g) was added and stirred for 1 h. The solutionwas filtered through celite and was evaporated under reduced pressure togive glucosamine double salt of HCA as colourless powder (3.5 g).

The analytical characteristics of the glucosamine salt of HCA thusobtained are, (−)-HCA is 46.30%, lactone is 8.3%, glucosamine is 30.3%and calcium is 8.25%. This salt contains 1.01% of chlorides.

EXAMPLE 2

Magnesium, glucosamine double salt of HCA: To an aqueous garciniasolution (27 mL, 2.0 g, 1.0 equivalent) was added glucosamine free basesolution (100 mL, 1.7 g, 1.0 equivalent) and stirred for 1 h. Thenmagnesium carbonate (0.93 g, 1.0 equivalent) was added and afterstirring for 2 h, charcoal (0.5 g) was added and stirred for 1 h. Thesolution was filtered through celite and stripped off water underreduced pressure to give magnesium, glucosamine double salt of HCA ascolourless powder (3.0 g).

The analytical characteristics of the glucosamine salt of HCA obtainedare, (−)—HCA: 49.80%, lactone: 6.3%, glucosamine: 31.3% and magnesium:5.5%. This salt contains 0.5% of chlorides.

EXAMPLE 3

Zinc, glucosamine double salt of HCA: To an aqueous garcinia solution(27 mL, 2.0 g, 1.0 equivalent) was added glucosamine free base solution(100 mL, 1.7 g, 1.0 equivalent) and stirred for 1 h. Then zinc carbonate(1.0 g, 1.0 equivalent) was added and after stirring for 2 h at rt,charcoal (0.5 g) was added and stirred for 1 h. The solution wasfiltered through celite and water was evaporated under reduced pressureto give zinc, glucosamine double salt of HCA as colourless powder (2.8g).

The analytical characteristics of the glucosamine salt of HCA obtainedare, (−)-HCA: 46.60%, lactone: 6.5%, glucosamine: 29.45% and zinc:10.2%. This salt contains 0.8% of chlorides.

EXAMPLE 4

Calcium, glucosamine double salt of HCA (KCl): A mixture of calcium,potassium salt of HCA (300 g, 1.0 molar equivalent, prepared by theprocedure described in Ganga Raju, G. PCT Publication No. WO 99/03464)and glucosamine hydrochloride (209 g, 1.0 molar equivalent) in 95%aqueous methanol (2.0 L) was stirred at rt for 5 h. The solid wasfiltered and washed with the same solvent (250 mL). The solid mass wasdried under vaccum at 60° C. for 5 h to give calcium, glucosamine doublesalt of HCA as colourless powder (495 g).

The analytical characteristics of the glucosamine salt of HCA thusobtained are, HCA: 40.10%, lactone: 0.37%, glucosamine: 36.81%, calcium:6.96% and potassium: 8.48%. This salt contains 7.50% of chlorides.

EXAMPLE 5

Calcium, norephedrine double salt of HCA: To an aqueous garciniasolution (27 mL, 2.0 g, 1.0 equivalent) was added norephedrine (1.4 g,1.0 equivalent) and stirred for 1 h. Then calcium hydroxide (708 mg, 1.0equivalent) was added and after stirring for 2 h, charcoal (0.5 g) wasadded and stirred for 1 h. The solution was filtered through celite andstripped off water under reduced pressure to give calcium, norephedrinedouble salt of HCA as colourless powder (2.7 g).

The analytical characteristics of the calcium, norephedrine double saltof (−)-HCA thus obtained are, HCA: 42.14%, lactone: 12.32%,norephedrine: 32.18% and calcium: 7.09%.

EXAMPLE 6

Magnesium, norephedrine double salt of HCA: To an aqueous garciniasolution (27 mL, 2.0 g, 1.0 equivalent) was added norephedrine (1.4 g,1.0 equivalent) and stirred for 1 h. Then magnesium carbonate (0.9 g,1.0 equivalent) was added and after stirring for 2 h, charcoal (0.5 g)was added and stirred for 1 h. The solution was filtered through celiteand water was evaporated under reduced pressure to give magnesium,norephedrine double salt of HCA as colourless powder (2.9 g).

The analytical characteristics of the magnesium, norephedrine doublesalt of HCA thus obtained are, HCA: 45.84%, lactone: 9.37%,norephedrine: 32.14% and magnesium: 5.62%.

EXAMPLE 7

Zinc, norephedrine double salt of HCA: To an aqueous garcinia solution(27 mL, 2.0 g, 1.0 equivalent) was added norephedrine (1.4 g, 1.0equivalent) and stirred for 1 h. Then zinc carbonate (1.0 g, 1.0equivalent) was added and after stirring for 2 h, charcoal (0.5 g) wasadded and stirred for 1 h. The solution was filtered through celite andwater was evaporated under reduced pressure to give zinc, norephedrinedouble salt of HCA as colourless powder (3.0 g).

The analytical characteristics of the zinc, norephedrine double salt ofHCA thus obtained are, HCA: 42.83%, lactone: 10.35%, norephedrine:30.47% and zinc: 10.2%.

EXAMPLE 8

Magnesium, sibutramine double salt of HCA: To an aqueous garciniasolution (27 mL, 2.0 g, 1.0 equivalent) was added sibutramine (2.6 g,1.0 equivalent) and stirred for 1 h. Then magnesium carbonate (0.9 g,1.0 equivalent) was added and after stirring for 2 h, charcoal (0.5 g)was added and stirred for 1 h. The solution was filtered through celiteand water was evaporated under reduced pressure to give magnesium,sibutramine double salt of HCA as colourless powder (3.5 g).

The analytical characteristics of the magnesium, sibutramine double saltof HCA thus obtained are, HCA: 38.58%, lactone: 10.16%, sibutramine:40.0% and magnesium: 3.52%.

The new compounds are used in reducing body weight and as a cure forarthritis. These compounds may be used as a dietary and nutraceuticalsupplements particularly in beverages.

1. A double salt of (−)-hydroxycitric acid with an amine and zinc or agroup II A metal having the following general formula.

Wherein X is zinc or a metal belonging to group II A of the PeriodicTable and Y is glucosamine or caffeine or a known anorexic amineresidue.
 2. The double salt as claimed in claim 1 wherein X is zinc orany group H A metal and Y is selected from glucosamine in free base formor glucosamine hydrochloride or other glucosamine salts.
 3. The doublesalt as claimed in claim 1 wherein X is selected from zinc or any groupII A metal and Y is selected from caffeine, norephedrine, sibutramineand oflaer anorexic amines.
 4. The double salt as claimed in claim 1,wherein X is selected from Zn, Be, Mg, Ca, Sr, Ba or Ra.
 5. The doublesalt as claimed in claim 1 wherein said anorexic amines are selectedfrom aminorex, clobenzorex, cyclexedrine, diphemethoxidine,fenbutrazate, fenproporex, furfuryl methylamphetamine,levophacetoperane, mefenorex, metamfepramone, norpseudoephedrine,pentorex, picilorex, sibutramine or phenylpropanolamine.
 6. A processfor the preparation of a double salt of (−)-hydroxycitric acid with zincor a group II A metal and a known amine of the general formula Icomprising the steps of slowly adding the amine to an aqueous extract ofhydroxycitric acid followed by the addition of a solution of group II Ametal compound or a zinc compound.
 7. The process as claimed in claim 6wherein said double salt is recovered from the reaction mixture eitherby removing water under reduced pressure or by adding a water misciblesolvent such as alcohols, acetone, acetonitrile, dioxan, tetrahydrofuranor mixtures thereof
 8. A process for the preparation of double salt of(−)-hydroxycitric acid of the general formula I comprising the steps ofdisplacing potassium or sodium from a calcium. votassium/sodium doublesalt of HCA by a known amine moiety in a known manner.
 9. The process asclaimed in claim 8, wherein said displacement is carried out in thepresence of water or a mixture of water and water miscible solvents. 10.The process as claimed in claim 9, wherein said water miscible solventsare alcohols, acetone, acetonitrile, dioxan, totrahydrofuran or mixturesthereof.
 11. The process as claimed in claim 9 wherein the water contentof the water miscible solvent is in the range of 5 to 50% preferably inthe range of 5 to 10%.
 12. The process as claimed in claim 6 whereinsaid double salt is separated from the reaction mixture by filtration.13. A process for preparing a double salt of (−)-hydroxycitric acid withanorexic amine compounds such as norephedrine or sibutramine and zinc orgroup II A metal compounds comprising the step of slowly adding 1.0molar equivalent of norephedrine or sibutramine to an aqueous extract ofhydroxycitric acid followed by adding 1.0 molar equivalent of zinc orgroup II A metal compound and recovering said double salt from thereaction mixture in a known manner.
 14. The double salt of (−)-HCA withAn ammie and zinc or a group II A metal according to claim 1 is morethan 80%, preferably higher than 95%.
 15. The double salt of (−)-HCAwith glucosamine and zinc or a group II A metal composition according toclaim 1 or 2 is approximately; HCA: 30-50%; lactone: 0.1-15%;glucosamine: 20-35%; calcium: 6-10% or magnesium: 4-8%; or zinc: 8-15%and chlorides: 0-2%.
 16. The double salt of (−)-HCA with glucosamine andzinc or a group II A metal (KCl) composition according to claim 1 or 2is approximately; HCA: 35-50%; lactone: 0.5-1.0%; glucosamine: 15-40%;calcium: 510%; potassium: 7-15% and chlorides: 2-8%.
 17. The double saltof (−)-HCA with norephedrine and a group II A metal compositionaccording to claim 1, comprises about 30 to about 40% of HCA; about 0.1to about 10% of lactone; about 20 to about 35% of norephedrine and about5 to about 10% of calcium.
 18. The double salt of (−)-HCA withsibutramine and a group II A metal composition according to claim 1,comprises about 20 to about 35% of HCA; about 0.1 to about 10% oflactone: about 20 to about 45% of sibutramine and about 2 to about 8% ofmagnesium.
 19. The double salt of (−)-HCA with an amine and zinc or agroup II A metal are tasteless, odourless and highly soluble in water.These are suitable for nutraceutical or beverage applications.
 20. Adouble salt (−)-hydroxycitric acid with an amine and zinc or a group IIA metal substantially as herein described.
 21. A process for preparing adouble slat of (1)-hydroxycitric acid with an amine and zinc or group IIA metal substantially as herein described and exemplified.
 22. Use ofdouble salt of (−)-hydroxycitric acid with an amine and zinc or a groupII A metal for reducing obesity and for the treatment of arthritis. 23.Use of double salt of (−)-hydroxycitric acid with an amine and zinc or agroup II A metal as dietary supplement, a nutraceufical and inbeverages.